Diphenyl Disulfide Induces Nonapoptotic Paraptosis in Breast Cancer Cells via ROS-Mediated ER Stress

Breast cancer is the most common cancer in women and a leading cause of cancer-related mortality worldwide. Most anticancer drugs act against cancer cells by inducing apoptotic pathways; unfortunately, chemoresistance, especially apoptosis resistance, contributes to poor outcomes in patients with breast cancer. Paraptosis is a type of nonapoptotic programmed cell death characterized mainly by cytoplasmic vacuolization and endoplasmic reticulum (ER)/mitochondrial swelling, which may provide a promising strategy for overcoming chemotherapy resistance. We investigated the effects of diphenyl disulfide (DPDS) on two breast cancer cell subtypes, MDA-MB-231 (triple-negative) and MCF-7 (luminal A). Our findings demonstrate that DPDS exerts significant cytotoxic effects on these two breast cancer cell lines. In addition, DPDS induced the accumulation of vacuoles in cells and downregulated the paraptosis marker Alix while increasing the expression of the ER stress markers BIP/Grp78 and IRE-1 and oxidative stress owing to the accumulation of reactive oxygen species (ROS), eventually inducing paraptosis. In contrast, pretreatment with N-acetylcysteine (NAC) significantly restored cell survival and reduced BIP expression. Our study highlights the potential of DPDS to target two cell death pathways, representing a novel therapeutic strategy for patients with breast cancer resistant to apoptosis-inducing therapies.